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Tricyclic diterpene analogue, preparation method of analogue and application of analogue in preparation of anti-prostate cancer drugs

A technology of tricyclic diterpene and analogs, which is applied in the preparation of anti-prostate cancer drugs. The field of tricyclic diterpene analogs and its preparation can solve the problems of inability to combine with anti-androgen drugs, lack of LBD domain, Drug resistance and other issues

Inactive Publication Date: 2017-07-07
EAST CHINA NORMAL UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

At the same time, AR-Vs lack a complete LBD domain, and anti-androgen drugs cannot bind to it. Because of this, AR-Vs show resistance to traditional anti-androgen therapy drugs (acting on the LBD domain)

Method used

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  • Tricyclic diterpene analogue, preparation method of analogue and application of analogue in preparation of anti-prostate cancer drugs
  • Tricyclic diterpene analogue, preparation method of analogue and application of analogue in preparation of anti-prostate cancer drugs
  • Tricyclic diterpene analogue, preparation method of analogue and application of analogue in preparation of anti-prostate cancer drugs

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0073] Embodiment 1: the preparation of compound shown in formula (4)

[0074]

[0075] The preparation of tricyclic diterpene analogs shown in formula (4), namely compound 4: compound 1 (10.0g, 36.5mmol), DMAP (558mg, 7.3mmol) were placed in a single-necked bottle, N 2 For replacement, 60 mL of anhydrous DCM was injected, and acetic anhydride (10.4 mL, 109.5 mmol) was slowly added dropwise. After the addition was complete, the mixture was stirred at room temperature for 4 h. TLC detects that the raw materials have reacted completely, slowly add 30mL of water dropwise, extract the aqueous phase with DCM (20mL×3), combine the organic phases, wash with water, wash with saturated NaCl solution, dry over anhydrous sodium sulfate, concentrate, and perform silica gel column chromatography (PE: EA=10:1), concentrated to give product 2 (11.42g white solid, 99.0%). 1 H NMR 400MHz, CDCl 3 )δ6.97(d, J=8.4Hz, 1H), 6.77(d, J=2.4Hz, 1H), 6.67(dd, J=8.4, 2.8Hz, 1H), 4.56(dd, J=11.2, 4.8...

Embodiment 2

[0080] Embodiment 2: formula (5), (6), (7), (8), (9), (10), (11), (12), (13), (14), (15), ( 16), preparation of tricyclic diterpene analogs shown in (17)

[0081]

[0082] Tricyclic diterpene analogs (5), (6), (7), (8), (9), (10), (11), (12), (13), (14), (15), The general synthetic method of (16), (17):

[0083] Compound (4) (150mg, 0.47mmol), EDCI (180.2mg, 0.94mmol), HOBt (127mg, 0.94mmol), DMAP (230mg, 1.88mmol) and heterocyclic amine (1.41mmol) were placed in a 50mL single-necked bottle , N 2 For replacement, inject 10ml of anhydrous DCM or anhydrous DMF, and stir at room temperature for 8h. TLC detected that the reaction of the raw materials was complete, added 10 mL of water, adjusted the pH of the system to <7 with dilute HCl, extracted the aqueous phase with DCM (10 ml×3), combined the organic phases, washed with water, washed with saturated NaCl solution, dried over anhydrous sodium sulfate, concentrated, and silica gel Column chromatography (DCM:MeOH=60:1), co...

Embodiment 3

[0097] Example 3: Anti-proliferation test of tricyclic diterpene analogues in prostate cancer cells

[0098] The SRB method was used to test the anti-proliferation activity of three prostate cancer cell lines (DU145, LNCap, 22RV1).

[0099] (1) Test principle

[0100] SRB (sulfonylrhodamine B) is a pink anionic dye that is easily soluble in water and can specifically combine with basic amino acids that make up proteins in cells under acidic conditions; it produces an absorption peak at a wavelength of 515nm. It has a good linear positive correlation with the cell amount and can be used as a quantitative detection of the cell number.

[0101] (2) Sample test

[0102] (1) The compound to be tested was dissolved in DMSO solvent to 20 mM and stored as a mother solution. (2) Tumor cells were seeded on a 96-well plate at an appropriate density, and after being cultured in a cell incubator for 24 hours, the cells were treated with different concentration gradients of the compound ...

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Abstract

The invention discloses a tricyclic diterpene analogue shown as formula (I) and a preparation method of the analogue. The preparation method comprises the following steps: taking a tricyclic diterpene analogue (1) as a raw material, carrying out an esterification reaction, a Friedel-Crafts acylation reaction, a haloform reaction, a hydrolysis reaction and an amidation reaction so as to prepare a compound (4); and taking the compound (4) as a raw material, carrying out the amidation reaction under catalysis of DMAP, EDCI and HOBt, thereby obtaining the tricyclic diterpene analogue shown as formula (I). The invention further provides application of the tricyclic diterpene analogue in preparation of anti-prostate cancer drugs. The structural formula is as shown in the specification.

Description

technical field [0001] The invention belongs to the technical field of medicine and its preparation and application, and in particular relates to a tricyclic diterpene analog, a preparation method thereof, and an application in preparation of anti-prostate cancer drugs. Background technique [0002] Prostate cancer is a malignant tumor of the urinary system that seriously threatens the health of middle-aged and elderly men. About 680,000 men are diagnosed with prostate cancer every year in the world, and 220,000 of them die from prostate cancer. In Europe, the incidence of prostate cancer in men has surpassed that of lung cancer and ranks first; in the United States, prostate cancer ranks second in the death rate of male cancer; in my country, the incidence of prostate cancer is increasing year by year. Once reached more than 10%. Prostate cancer has no obvious symptoms in the early stage. It is often found that the value of PSA increases during physical examination, and it ...

Claims

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Application Information

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IPC IPC(8): C07D231/56C07D277/82C07D277/62C07D209/08C07D235/30C07D277/46C07D213/75C07C27/02C07C65/26A61P35/00A61P13/08
CPCC07D231/56C07C51/09C07C67/08C07C67/293C07D209/08C07D213/75C07D235/30C07D277/46C07D277/62C07D277/82C07C69/157C07C65/26
Inventor 仇文卫易正芳汪炎彭世鸿刘明耀谢佳
Owner EAST CHINA NORMAL UNIV
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